US4254107AExpiredUtility
Long-lasting agonists of enkephalin

Assignee: MERCK & CO INCPriority: Nov 27, 1979Filed: Nov 27, 1979Granted: Mar 3, 1981
Est. expiryNov 27, 1999(expired)· nominal 20-yr term from priority
Inventors:Daniel F. Veber Roger M. Freidinger
C07D 207/273C07D 279/06C07K 14/702C07D 223/12A61K 38/00
PatentIndex Score
Cited by
References
Claims
Abstract

Novel peptides of the formula: <IMAGE> wherein X is S or (CH2)n and n is 0, 1 or 2, and R1 through R6 are various amino acid and other substituents; having long-lasting enkephalin agonist activity; useful in treating pain and in treating schizophrenia.
Claims

exact text as granted — not AI-modified
What is claimed is: 
     
       1. A novel peptide of the formula: ##STR15## where, unless otherwise indicated, an amino acid substituent identified below has the &#34;S--&#34; stereoconfiguration: X is S or (CH 2 ) n , where n is 0, 1 or 2;   R 1  is hydrogen; C 1-6  alkyl; H-Arg; or H-Lys-Arg;   R 2  is hydrogen; C 1-6  alkyl; or, when R 1  is hydrogen, may be allyl or cyclopropylmethyl;   R 3  is hydrogen or methyl;   R 4  is benzyl; benzyl substituted with halo, nitro, hydroxy, amino, C 1-4  alkyl, or cyano; indolylmethyl; imidazolylmethyl; or isopropylmethyl;   R 5  is hydrogen or methyl;   R 4  and R 5  taken together are phenylmethylene; and   R 6  is (a) OM, where M is hydrogen, C 1-6  alkyl, or a cation; (b) NR 7  R 8 , where R 7  and R 8  are independently selected from the group consisting of hydrogen; C 1-6  alkyl, and, when either of R 7  or R 8  is hydrogen, --CH 2  CH 2  N(CH 3 ) 2  and ##STR16##  (c) (Met-OH; (d) Met-NH 2  ; (e) Met-ol; (f) D-Met-NH 2  ; (g) N-methyl-Met-NH 2  ; (h) Met(O)-NH 2  ; (i) Met(O)-ol; (j) Leu-NH 2  ; (k) N-methyl-Leu-NH 2  ; (1) D-Leu-NH 2  ; or (m) Pro-NH 2 .   
     
     
       2. A peptide according to claim 1 wherein: X is S or (CH 2 ) n  where n is 1 and the resulting lactam has an &#34;R&#34; steroconfiguration; and   R 1  and R 2  are hydrogen;   R 3  and R 5  are hydrogen or methyl;   R 4  is benzyl;   R 4  and R 5  taken together are phenylmethylene; and   R 6  is NR 7  R 8  where one of R 7  or R 8  is hydrogen and the other is --CH 2  CH 2  N(CH 3 ) 2  or ##STR17##  Met-OH; Met-NH 2  ; Met-ol; D-Met-NH 2  ; N-methyl-Met-NH 2  ; Met(O)-NH 2  ; Met(O)-ol; Leu-NH 2  ; N-methyl-Leu-NH 2  ; D-Leu-NH 2  ; or Pro-NH 2 .   
     
     
       3. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[N-methyl-Phe]-Met-NH 2 . 
     
     
       4. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[Nmethyl-Phe]-Met-ol. 
     
     
       5. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[N-methyl-Phe]-Met(O)-NH 2 . 
     
     
       6. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[N-methyl-Phe]-Met(O)-ol. 
     
     
       7. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[N-methyl-Phe]-N-methyl-Met-NH 2 . 
     
     
       8. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[N-methyl-Phe]-D-Met-NH 2 . 
     
     
       9. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[N-methyl-Phe]-Leu-NH 2 . 
     
     
       10. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[Nmethyl-Phe]-N-methyl-Leu-NH 2 . 
     
     
       11. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[N-methyl-Phe]-D-Leu-NH 2 . 
     
     
       12. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[N-methyl-Phe]-Pro-NH 2 . 
     
     
       13. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[N-methyl-Phe] ##STR18## 
     
     
       14. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[N-methyl-Phe]-NH-CH 2  CH 2  N(CH 3 ) 2 . 
     
     
       15. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[α-methyl-Phe]-Met-NH 2 . 
     
     
       16. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[α-methyl-Phe]-Met-ol. 
     
     
       17. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[α-methyl-Phe]-Met(O)-NH 2 . 
     
     
       18. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[α-methyl-Phe]-Met(O)-ol. 
     
     
       19. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[α-methyl-Phe]-N-methyl-Met-NH 2 . 
     
     
       20. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[α-methyl-Phe]-D-Met-NH 2 . 
     
     
       21. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[α-methyl-Phe]-Leu-NH 2 . 
     
     
       22. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[α-methyl-Phe]-N-methyl-Leu-NH 2 . 
     
     
       23. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[α-methyl-Phe]-D-Leu-NH 2 . 
     
     
       24. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[α-methyl-Phe]-Pro-NH 2 . 
     
     
       25. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[α-methyl-Phe] ##STR19## 
     
     
       26. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[α-methyl-Phe]-NH-CH 2  CH 2  N(CH 3 ) 2 . 
     
     
       27. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[2,3-dehydro Phe]-Met-NH 2 . 
     
     
       28. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[2,3-dehydro Phe]-Met(O)-ol. 
     
     
       29. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-2,3-dehydro Phe]-N-methyl-Leu-NH 2 . 
     
     
       30. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[2,3-dehydro Phe] ##STR20## 
     
     
       31. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(3-amino-2-oxo-1-piperidine)acetic acid]-[2,3-dehydro Phe]-NH-CH 2  CH 2  N(CH 3 ) 2 . 
     
     
       32. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R(5-amino-4-oxo-1,3-thiazine)acetic acid]-[N-methyl-Phe]-Met-NH 2 . 
     
     
       33. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(5-amino-4-oxo-1,3-thiazine)acetic acid]-[N-methyl-Phe]-Met(O)-ol. 
     
     
       34. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R(5-amino-4-oxo-1,3-thiazine)acetic acid]-[N-methyl-Phe]-N-methyl-Leu-NH 2 . 
     
     
       35. A peptide according to claim 1 wherein the peptide is H-Tyr-2-[R-(5-amino-4-oxo-1,3-thiazine)acetic acid]-N-methyl-Phe] ##STR21## 
     
     
       36. A peptide according to claim 1 wherein the peptide is H-Tyr-2[R-(5-amino-4-oxo-1,3-thiazine)acetic acid]-[N-methyl-Phe]-NH-CH 2  CH 2  N(CH 3 ) 2 . 
     
     
       37. A pharmaceutical composition for treating pain comprising a non-toxic, pharmaceutically acceptable carrier and a therapeutically effective amount of a peptide of the formula: ##STR22## where, unless otherwise indicated, an amino acid substitutent identified below has the &#34;S--&#34; stereoconfiguration: X is S or (CH 2 ) n , where n is 0, 1 or 2;   R 1  is hydrogen; C 1-6  alkyl; H-Arg; or H-Lys-Arg;   R 2  is hydrogen; C 1-6  alkyl; or, when R 1  is hydrogen, may be allyl or cyclopropylmethyl;   R 3  is hydrogen or methyl;   R 4  is benzyl; benzyl substituted with halo, nitro, hydroxy, amino, C 1-4  alkyl, or cyano; indolylmethyl; imidazolylmethyl; or isopropylmethyl;   R 5  is hydrogen or methyl;   R 4  and R 5  taken together are phenylmethylene; and   R 6  is (a) OM, where M is hydrogen, C 1-6  alkyl, or a cation; (b) NR 7  R 8 , where R 7  and R 8  are independently selected from the group consisting of hydrogen; C 1-6  alkyl, and, when either of R 7  or R 8  is hydrogen, --CH 2  CH 2  N(CH 3 ) 2  and ##STR23##  (c) Met-OH; (d) Met-NH 2  ; (e) Met-ol; (f) D-Met-NH 2  ; (g) N-methyl-Met-NH 2  ; (h) Met(O)--NH 2  ; (i) Met(O)-ol; (j) Leu-NH 2  ; (k) N-methyl-Leu-NH 2  ; (l) D-Leu-NH 2  ; or (m) Pro-NH 2 .
Cited by (0)

No later patents cite this yet.
References (0)

No backward citations on record.